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CROI Summary 2012
Inflammation, metabolic complications and strategies for eradication.
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Pablo Tebas
University of Pennsylvania
Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.
Sir Winston Churchill, Speech in November 1942.
This year the CROI meeting took place in Seattle, a beautiful, vibrant and multicultural city. The weather was better than the usually expected grey and rain. This was a different CROI meeting. Although we still saw the results of some large randomized trials (like the QUAD studies), the scientific focus was different: there was a lot about "treatment as prevention" and PREP, tuberculosis and hepatitis C. I will leave to others talking about those topics.
In the basic science, the big themes of the meeting were the structural characterization of neutralizing antibodies against HIV, the study of cellular factors that help to block HIV infection in vivo: TRIM5alpha, TREX1 and SAMHD1 and how HIV gets around those mechanisms. In the clinical and therapeutic side the focus was for the first time in strategies for eradication. I had the feeling that something was changing in this retrovirus meeting. Traditionally this meeting has been the avenue to present large randomized therapeutic trials. Although there was some of that (the QUAD studies, the dolutegravir phase II, the new and improved tenofovir, etc); this time the focus was in small proof of concept studies. We were shown for the first time that it's possible to reactivate HIV infection from latency in HIV-infected individuals using histone deacetylase inhibitors (SAHA). Whether this reactivation makes the cells that harbors HIV virus "visible" to the immune system is the big question, although we saw that, at least in vitro, it is possible to target those cells.
We have not cured HIV, but there are a heck of very smart people thinking about it, and it is very exciting. In Seattle there was a general feeling that we are entering a new era in research about this disease. These themes are going to dominate the meeting for the next few years. I think we are just at the very beginning of this new field, and that is why I decided to use the famous quote from Winston Churchill.
I will focus my review of some studies presented about inflammation and metabolic complications (fields that have come close together lately) and around the theme of eradication.
Inflammation/metabolic complications
There was a whole symposium, the last of the meeting (The Long and Winding Road of HIV Complications), about the classic metabolic complications of HIV infection and its treatment, including aging, bone, cardiovascular disease and neurological complications. It is worth seeing it (you can do it online for free at http://retroconference.org/static/webcasts/2012/). The tone of the symposium was somewhat subdued because the main message was a word of caution, suggesting that what is happening to HIV infected individuals, although may be unique in many ways, it is not much different from what's happening in the general population, and that we should be careful to quickly attribute to HIV or its treatment many of the complications that we are seeing in our patients. Our patients are part of the society and the culture that we live in, and much of what we see is just a reflection of the combination of regular aging and traditional risk factors. We still need to do studies to understand better how much of it is related to HIV itself and its treatment.
(from Jules: the oral talk by Judith Currier on 'HIV Complications' was I thought more on target)
http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20481&&dp=player.jsp&e=16600&mediaType=podiumVideo
CROI 2012: Studies on Inflammation in HIV - written by David H. Shepp, MD Associate Professor of Medicine Hofstra North Shore-LIJ School of Medicine North Shore University Hospital - Manhasset, NY - (03/16/11)
The presentation of the two QUAD studies allowed us to compare the lipid effects of efavirenz and atazanavir to cobicistat/elvitegravir, which certainly will become a popular first choice when it is approved in the summer of 2012 1-2. Efavirenz (with tenofovir and FTC) is associated with greater increases in lipids, particularly cholesterol and LDL when compared to the elvitegravir/cobicistat combination1. The Quad pill is associated with similar changes in cholesterol to a combination with boosted atazanavir, but the latter increases more triglycerides 2. In general the changes in lipids are not very dramatic with any combination and I do not know how much the decision of what to start in a naive patient will be driven by these changes in lipid parameters, rather than antiviral efficacy, cost and other side effect profile.
CROI: Antiretroviral Therapy at CROI - PHASE III, PHASE II, PHASE I -written by Joseph Eron MD Professor of Medicine University of North Carolina at Chapel Hill - (03/19/11)
CROI: The Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF ("Quad") Compared to Efavirenz/Emtricitabine/Tenofovir DF in Treatment Nave HIV-1 Infected Subjects: Primary Results of Study GS-US-236-0102 - (03/8/11)
CROI: Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF "Quad" Compared to Ritonavir-boosted Atazanavir plus Emtricitabine/Tenofovir DF in Treatment Naive HIV-1 Infected Subjects - (03/9/11)
CROI: Dolutegravir ViiV Integrase Inhibitor phase 2b SPRING Study 96-Week Results in Treatment-Naives - (03/8/11)
Esteban Martinez presented data from the SPIRAL3 study looking at the changes in lipids and markers of inflammation after switching from a boosted protease inhibitor to raltegravir. There were clear improvements particularly in triglycerides and cholesterol and in several biomarkers that have been traditionally associated with cardiovascular disease and insulin resistance. This type of "switch approach" may be important for the management of patients that have difficulty controlling some of those parameters while receiving treatment with a boosted protease inhibitor. An integrase inhibitor like raltegravir is definitely more lipid friendly. However, it is important to remember that all switches have to be done with caution particularly if the patient that has had prior virological failure.
CROI: Changes in Cardiovascular Biomarkers in Subjects Switching from Ritonavir- Boosted Protease Inhibitors to Raltegravir: The SPIRAL Study - (03/20/11)
Atazanavir is probably the most lipid friendly of the protease inhibitors (maybe not very different from darunavir -although not a lot of that that was presented in the meeting-). In another analysis of the DAD study4, the use of atazanavir was not associated with an increased risk of myocardial infarction, something that had happened before with lopinavir and indinavir. The news was reassuring as atazanavir is the most popular of the protease inhibitors of the present time.
We thought for a while that the use of CCR5 antagonists, like maraviroc, will be associated with improvements in cardiovascular function. Priscilla Hsue from the San Francisco group presented data in a randomized trial that added maraviroc (or not) to individuals with well controlled viral replication5-6. In this study the addition of maraviroc was not associated with improvements in flow mediated dilatation, a surrogate marker of progression of cardiovascular disease.
Surprisingly, the use of maraviroc was associated with an increase in markers of inflammation of monocytes and macrophages (sCD14). The investigators showed that this was associated with increases in the natural ligands of CCR5 (that mediate inflammation in monocytes). The study clearly shows the complexity of the immune system, and that blocking a particular receptor sometimes can lead to unexpected distant consequences in a cascade effect that it is difficult to predict.
What can we do about this persistent inflammation despite virological control that patients with HIV infection suffer? Should all patients with HIV infection take a statin or aspirin? Turner Overton looked at the experience in the ACTG, in the massive ALRT study7. The use of statins seemed to be associated with a decrease in non-AIDS events and mortality after controlling for traditional risk factors. The benefits were more obvious in older individuals. Although the study is retrospective, a lot of care was placed in controlling for bias statistically. I think the overall conclusion is that it may be possible to do simple interventions in HIV patients with persistent inflammation despite of antiretroviral treatment to address this problem. The Jupiter study8, published two years ago in the New England Journal of Medicine, suggests that individuals with chronic inflammation may benefit from the use of statins beyond the direct effect of these drugs in lipids. Patients with HIV infection might represent a similar population "at risk" for bad outcomes. I think prospective studies evaluating statins for this indication in HIV infected patients are needed, but I do not know who is going to pay the bill for doing them. Studies looking at clinical endpoints are not particularly exciting; they require a large sample size and long-term follow-up. In this era of shrinking budgets, it seems unlikely that anybody would swallow the pill (figuratively) and do what needs to be done.
CROI: Effect of Statin Therapy on Reducing the Risk of Serious Non-AIDS-Defining Events and Non-Accidental Death in the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) Cohort - (03/11/11)
CROI: ACEi or HMG-CoA Reductase Inhibitor (Statin) Treatment as Adjunct Therapy for Persons with HIV infection: A Pilot Study - (03/20/11)
There was less new data about bone problems. Starting tenofovir was associated with increased bone turnover in the PREPARE study9. The use of tenofovir is also associated with modest increases in creatinine10, something we already knew and that was also seen in individuals using some boosted protease inhibitors.
However these changes were modest and I do not think that we are going to see an epidemic of severe kidney failure in patients with HIV infection associated with antiretroviral treatment. I think it is important to monitor the kidney function of patients, particularly those at high risk, including the elderly, and individuals with comorbidities that could affect kidney function like hypertension or diabetes.
CROI: CROI Report: Bones, Frailty, and Vitamin D -written by Todd Brown, MD, PhD Associate Professor of Medicine Division of Endocrinology and Metabolism Johns Hopkins University - (03/19/11)
Persistence, latency and eradication
There was a very interesting session (Oral Abstract: HIV Persistence, Latency, and Eradication) that I think people will refer to in the future, because it presented a good picture of the current state of affairs and the first evaluations of different approaches that are being taken with the ultimate purpose of eradicating HIV infection.
In general two different approaches have been tried so far to eradicate HIV. The first approach is to identify each of the HIV reservoirs and to try find ways to eliminate them by activating the latently infected cells, with the hope that that activation will lead to the death of the infected cell, or that the expression of HIV RNA and proteins will make that particular cell "visible" to the immune system, and that by doing that the immune system will be able to eliminate the reservoir. The alternative approach is to modify the immune system of the individual patient and make it resistant to HIV infection. In this direction several gene therapy approaches have been undertaken, some of them using mature T lymphocytes, and others trying to modify genetically stem cells.
The other general approach is to try to get to what many people have called "functional cure". Maybe we will not be able to eliminate every single HIV reservoir, but the immune system may be able to control HIV infection to the same degree that antiretroviral therapy does. Different groups are trying therapeutic vaccines, -which had a surprising comeback during this meeting-, and other groups are trying the use of immunomodulators, like interferon.
During the session Maria Buzon from Harvard presented data that suggest that the earlier an individual initiates antiretroviral therapy the smaller the size of the reservoir is11 (and maybe easier to eliminate). If antiretroviral therapy is initiated during acute seroconversion the size of the reservoir becomes similar to the reservoir of elite controllers. Trying to reduce the size of the reservoir is another argument to start antiretroviral therapy early in the course of HIV infection (if anybody needed another argument for that).
I think one of the most important presentations of the session was from Lian Shan from the group of Bob Siliciano at John Hopkins University12. They used small molecules (histonedeacetylases (HDACs), like SAHA and others) to reverse latency in vitro and then they showed that a "stimulated" CTL response is capable of "seeing" those cells and eliminate them. They demonstrated that the CTL response of the HIV infected individual by itself is insufficient to eliminate the infected cells, but that those CTL cells can be stimulated in vitro to target the HIV infected cells. Of course, the main issue is to translate this observation into a living and breathing human without harm Šsomething much easier said than done-. However these results are unbelievably promising and show a potential pathway to move forward.
New HIV Eradication Research paper Published by Siliciano et al: Johns Hopkins breakthrough may end AIDS patients' need for lifelong drugs below - (03/11/12)
At this point we do not know why Tim Brown was cured from HIV infection. We do not know if it was the very aggressive chemotherapy that he received to treat his acute leukemia, the fact that he received an allogenic bone marrow transplant from a Delta 32 homozygous donor that could not support HIV replication, or the fact that he developed graft versus host disease after the bone marrow transplantation. It might have been a combination of those possibilities. The group from John Mellors from Pittsburgh tried to dissect the different possibilities one at a time. They presented data on what happens to the size of the reservoir in individuals that have received chemotherapy because of a malignancy 13 and also in individuals that have received a stem cell implantation for lymphoma14. They measured the size of the reservoir using the single copy assay and they demonstrated that neither chemotherapy not bone marrow transplantation makes the reservoir disappear. Both groups of individuals maintained levels of the reservoir (measured by the single copy assay) after the intervention. This is not good news and clearly shows the difficulties ahead to eradicate HIV. Unfortunately, the more data is presented, the more it seems that the graft versus host disease that Tim Brown developed after his bone marrow transplant played an important role in the complete removal of his HIV reservoir. We know the graft versus host is very important to eliminate leukemic cells and cure patients with that disease, so it is not a big leap of faith to think that the donor cells "saw" the remaining cells from the reservoir as foreign and eliminated them. Of course, if that was the main mechanism, it will complicate strategies for eradication, as graft versus host disease is definitely worse than the treatment of well controlled HIV infection.
CROI: Incomplete HIV Control During ART Triples Risk of non-Hodgkin Lymphoma - written by Mark Mascolini - (03/16/11)
We presented final data of our study, using gene therapy to modify the CD4 cells by removing the CCR5 using zinc finger nucleases. We had presented preliminary data of this study during ICAAC in the fall 2011. In HIV infected, CD4 immune non-responders and responders on HAART, the infusion of these genetically modified cells was safe and well-tolerated with minor reversible symptoms. There were increases in total CD4 T-cells and normalization of CD4:CD8 ratio. There was a dramatic expansion of the infused cells probably related to increases in IL-2, -7 and -15 associated with the infusion of the cells. In the cohort of the University of Pennsylvania we did a treatment interruption in 6 patients and we saw decreases of the peak viral load, and one patient, who was a Δ32 heterozygous, became undetectable in the absence of antiretroviral therapy at the end of the 12 weeks of treatment interruption. The frequency of biallelic CCR5 modification correlated with HIV-RNA suppression. The results of these studies are very promising and warrant further evaluation of ZFN-mediated gene-disruption of CCR5. There are ongoing studies evaluating these technologies in the treatment of CCR5 Δ32 heterozygous patients and in combination with the use of lymphopenic conditioning with mild chemotherapy to create "space" to allow these genetically modified cells to expand. Other groups in California are trying to modify stem cells using a similar technology. Like in other areas in this nascent field, we are watching the results of the first trials, and we still have a long way to go.
David Margolis presented the first study in well controlled HIV-infected individuals using Vorinostat (SAHA), to evaluate if this molecule is capable of reactivating HIV from latency. HDACs (histonedeacetylases) are responsible, at least in part, for keeping HIV "latent". The idea is to give inhibitors of these HDACs to reactivate HIV. His group gave a single dose of the vorinostat to HIV-infected individuals, and they were able to demonstrate an increase of HIV RNA in those cells. This is the first demonstration of an in vivo disruption of latent HIV infection, and it was definitely one of the highlights of the meeting. The next question is: does this activation make those cells "different" and "visible" to the immune system so they can be targeted and eliminated? We simply do not know, although the data from Siliciano lab, summarized above suggest that it may be possible. But before we reach that point we need to be sure that the use of these drugs is safe in our patients. The drugs need to be given more than a single time. There is a group in Australia treating patients with HIV with two weeks of vorinostat. The results of that trial will be available later this year. Other molecules with similar effects are also being tested in patients (romudepsin, prostatin etc).
CROI: David Margolis, UNC researchers find cancer drug that may help fight HIV - (03/14/11)
CROI: HIV Latency and Eradication at CROI 2012 -written by David Margolis, MD University of North Carolina - (03/19/11)
A different approach to the issue of virological control in the absence of therapy has been taken by the group lead by Luis Montaner of the Wistar Institute17-19. They used interferon alpha for five weeks in combination with antiretroviral therapy, and then they discontinued antiretroviral therapy and left the 22 participants in the trial only on weekly interferon alpha. A significant proportion of individuals were capable of maintaining virological suppression (45%) in spite of the absence of traditional antiretroviral therapy. Surprisingly, the individuals that maintained viral suppression had a significant decline in HIV integration levels after 12 weeks of monotherapy, when comparing those levels to baseline. The effects on the reservoir were associated with improvements in NK cell function. The administration of interferon alpha was safe and relatively well tolerated. It remains to be determined if the observed reduction in reservoir size was due solely to a direct effect of IFN-α (i.e. independent of ART interruption), or if a period of monotherapy with low-level viral replication that they also observed is also required to trigger immune responses that can affect reservoir size. The study suggests that the use of immunomodulators could affect the reservoir size.
Conclusions
This was an incredible meeting. It reminded me -in a different way because at that time it was a question of life and death- of some of the HIV meetings is in the mid 90s, when we started to see studies about the use of protease inhibitors for the treatment of HIV and the remarkable comebacks the patients were experimenting. Everybody had the feeling that the tide was changing then. In Seattle, I had a similar feeling because for the first time we were presented data and we were talking openly about the possibility of curing HIV infection.
Will see what happens.
References
1. Sax P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 101
2. DeJesus E, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. H 627
3. Martinez E, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 834.
4. D'Arminio Monforte A, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 823.
5. Hsue P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Absts. 123
6. Hsue P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Absts. 828
7. Overton E, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 124.
8. Ridker et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med 2008; 359:2195-2207
9. Cotter A, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 125LB
10. Ryom L, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 865.
11. Buzon M et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst.151.
12. Shan, L, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 153.
13. Cillo, A et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 353.
14. Cillo, A et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 154.
15. June, C et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 155.
16. Margolis, D et al.
17. Azzoni, L et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 631.
18. Papasavvas, E et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 93.
19. Mexas, A et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 374.
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